Delta-9-tetrahydrocannabinol (Δ9-THC) was isolated and identified as the major active constituent of marijuana in 1964 by Mechoulam and coworkers (Gaoni et al., J. Am. Chem. Soc. 86:1646 (1964)). In the following decades, the CB1 and CB2 receptors were discovered, characterized and shown to be responsible for the actions of Δ9-THC (Gernard et al., Biochem. J. 279:129 (1991); Skaper et al., Proc. Natl. Acad. Sci. USA 93:3984 (1996); Matsuda et al., Nature 346:61 (1990); Munro et al., Nature 365:61 (1993)). The CB1 and CB2 receptors have since gained attention as potential therapeutic targets for the development of antiobesity (Di Marzo et al., Nature 410:822 (2001)), anticancer (Palolaro et al., Prostaglandins Leukot. Essent. Fatty Acids 66:319 (2002)), analgesic (Palmer et al., Chem. Phys. Lipids 121:3 (2002)), and antiglaucoma agents (Porcella et al., Eur. J. Neurosci. 13:409 (2001); Chien et al., Arch. Ophthalmol. 121:87 (2003)). Efforts to develop therapeutic agents have resulted in the identification of a number of structurally distinct classes of compounds that bind to the cannabinoid receptors, these include the classical cannabinoids (Δ9-THC), the non-classical cannabinoids such as CP55,940 (Melvin et al., Med. Chem. 27:67 (1984)), the diarylpyrazoles such as AM-251 (Lan et al., J. Med. Chem. 42:769 (1999)), and aminoalkylindoles such as WIN-55212 (D'Ambra et al., J. Med. Chem. 35:124 (1992)). By far the most extensively studied cannabinoid analogs in terms of the pharmacology and SAR are the classical and non-classical cannabinoids.
The binding affinity of the classical cannabinoids (CCBs) and non-classical cannabinoids to the CB1 receptor can generally be defined in terms of a three point and four point pharmacophore model, respectively (Seltzman, Curr. Med. Chem. 6:685 (1999)). The structural elements that form the three point pharmacophore of the CCB analogs are: (1) a phenolic group in the C1 position of the aromatic ring (Razdan, Pharmac. Rev. 38:75 (1986); Uliss et al., J. Med. Chem. 18:213 (1975)); (2) an unsaturated Δ8 or Δ9 C ring with an exocyclic C11 methyl or hydroxy methyl, or alternatively a saturated C ring containing a 9-β-hydroxyl, 9-β-hydroxy methyl, or 9-keto functional group (Thomas et al., Mol. Pharmacol. 40:656 (1991); Wilson et al., J. Med. Chem. 19:1165 (1976); Melvin et al., Mol. Pharmacol. 44:1008 (1993); Mechoulam et al., Experientia 44:762 (1988); and (3) a C3 aliphatic side chain ranging from 3 to 7 carbons wherein heptyl analogs represent the optimum side chain length. In addition to the basic pharmacophore model, substitution of the C3 side chain with 1′,1′-dimethyl, 1′,2′-dimethyl, and 1′,1′-dithiolane generally enhances the activity of the CCBs (Huffman et al., Tetrahedron 53:1557 (1997); Huffman et al., Bioorganic Med. Chem. Lett. 7:2799 (1997); Guo et al., J. Med. Chem. 37:3867 (1994); Devane et al., J. Med Chem. 35:2065 (1992); Tius et al., Life Sci. 56:2007 (2007); Huffman et al., J. Med Chem. 39:3875 (1996)).
The understanding of the interplay between the pharmacophoric elements of CCBs and the ligand binding pocket (LBP) have been significantly refined as a result of QSAR studies and site directed mutagenesis of the LBP. Computational studies have identified the requirement for a hydrogen bond donor/acceptor pair in the C1 region of CCBs (Thomas et al., Mol. Pharmacol. 40:656 (1991); Schmetzer et al., J. Computer-Aided Mol. Design 11:278 (1997); Reggio et al., J. Med. Chem. 32:1630 (1989); Johnson et al., Cannabinoids as Therapeutic Agents, Boca Raton, Fla., CRC Press (1986)), a result proposed to correlate with an interaction of the C1 hydroxyl with a critical Lys192 in the CB1 receptor (Song et al., Mold. Pharmacol. 49:891 (1996); Chin et al., J. Neurochem. 70:280 (1998)). An additional donor/acceptor pair between Tyr275 and the CCBs containing a hydroxyl in the C9 region may be responsible for the increased CB1 affinity relative to Δ9-THC (McAllister et al., Biochem. Pharmacol. 63:2121 (2002), which is hereby incorporated by reference in its entirety).
The intramolecular geometries of the C1 and C9 substituents are tightly defined by the rigid ring system of the CCBs, however QSAR studies indicate moderate to high conformational flexibility in the C3 side chains (Schmetzer et al., J. Computer-Aided Mol. Design 11:278 (1997); Papahatjis et al., J. Med. Chem. 41:1195 (1998); Ryan et al., Life Sci. 56:2013 (1995); Keimowitz et al., J. Med. Chem. 43:59 (2000). These studies clearly demonstrate the LBP of CB1 prefers a hydrophobic substituent at C3 but the requirement for conformational flexibility remains to be fully elucidated. Progress to this end has been reported in studies of a series of conformationally restricted Δ8-THC side chain analogs incorporating methylene and methyne functionalities (Keimowitz et al., J. Med. Chem. 43:59 (2000)) and 1′-cyclopropyl analogs (Papahatjis et al., Bioorg. Med. Chem. Lett. 12:3583 (2002)). The study suggests that the side chain adopts an orthogonal geometry relative to the plane of the aromatic ring with the tail of the side chain folding into a hydrophobic pocket. Despite the incorporation of unsaturation into the side chains, considerable flexibility remains in this set of molecules. The inherent computational limitations in predicting the conformation of a flexible side chain, in the absence of x-ray crystallographic or high resolution NMR data, somewhat limits the ability to predict the preferred side chain geometry and LBP steric requirements of the CB receptors.
There still remains a need for identifying compounds that can be used for therapeutic purposes to affect treatment of conditions or disorders that are mediated by the CB-1 receptor and/or the CB-2 receptor.
The present invention is directed to developing Δ8-THC, Δ9-THC, and Δ6a-10a-THC analogs that exhibit activity, either as an agonist or an antagonist, on the CB-1 receptor and/or the CB-2 receptor and can be used to treat conditions or disorders that are mediated by these receptors.